Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality in women in the US but little is known of its etiology. Mitochondria participate in a number of essential functions in the cancer cell. The mitochondrial genome consists of a circular mitochondrial DNA (mtDNA) of 16.5 kilobases and approximately 1500 nuclear mitochondrial genes. Germline and somatic mitochondrial genome variants and mutations have been identified in a number of different cancers. However, very few studies have investigated the mitochondrial genome in EOC. We have performed genome-wide association studies (GWAS) and found a significant number of single nucleotide polymorphisms (SNPs) associations at the significance level (p<10-4 but >10-8) in genes showing significant associations in oxidative phosphorylation, epithelial-mesenchymal transition and apoptosis pathways, where the mitochondria plays a key role. The common element of the central role of mitochondria in the three pathways showing significant associations provides evidence of cross-talk between the mitochondrial and nuclear genomes, which warrants further investigation. We previously identified associations with ovarian cancer risk in apoptosis-related and EMT-related genes. Taken together, these results prompted this study, the GOAL of which is to more comprehensively investigate the contribution of mitochondrial genome variation to ovarian cancer risk. Nuclear mitochondrial gene variation, mtDNA haplotype analysis and correlative somatic mtDNA studies will be performed. These studies will enable us to fully evaluate the HYPOTHESIS that inherited variation in the mitochondrial genome as well as the nuclear genome should be considered as factors for risk of epithelial ovarian cancer. The specific aims are: 1) Stage 1 - To investigate SNPs in nuclear mitochondrial-related and mtDNA genes. 2) Stage 2 - To validate the top hits in nuclear mitochondrial-related genes and mtDNA genes in an independent case-control collection 3) To identify mtDNA mutations and variants in EOC. This study is novel as we are investigating both nuclear and mitochondrial variation as risk factors for ovarian cancer. There are few current studies on mitochondria and ovarian cancer. The results of this study will contribute significantly to our broader efforts to elucidate the genetic basis of ovarian cancer and unravel the complexities of this lethal disease.